Mechanisms of pituitary adenylate cyclase activating polypeptide (PACAP)-induced depolarization of sympathetic superior cervical ganglion (SCG) neurons.

Our understanding of PACAP expression and regulation of sympathetic neuronal function has been augmented considerably over the last few years. Among the three major VIP/PACAP receptor subtypes, the SCG appears to express preferentially one particular variant of the PACAP-selective PACAP1 receptor coupled to multiple intracellular signaling cascades. The in situ histochemical hybridization and immunocytochemical studies of PACAP1 receptor mRNA and protein are in good agreement; nearly all of the SCG neurons express the PACAP-selective receptor, suggesting that most of the sympathetic neurons are under PACAP neuromodulation. In accord with that possibility, several independent studies have now demonstrated PACAP peptide expression in the IML sympathetic preganglionic neurons and fibers, including those projecting to the SCG, further emphasizing the significance of PACAP peptides as a preganglionic noncholinergic mediator of sympathetic function. Given the high potency of PACAP on any of a number of cellular responses, the functional relevance of PACAP peptides on SCG neurons is considerable. We have previously demonstrated the potency and efficacy of both PACAP27 and PACAP38 on sympathetic neuron neurotransmitter/neuropeptide production and secretion; the ability of these peptides to stimulate neuronal second messenger activation was also in the nanomolar range. These results are congruous with our current electrophysiological studies, which were driven to further define the dynamic sympathetic responses to PACAP. In line with the morphological studies, for example, more than 90% of the sympathetic neurons responded to PACAP. In agreement with previous neuropharmacological data, the PACAP-induced depolarizations were elicited at physiologically relevant peptide concentrations at high affinity PACAP-selective receptors. The effects were direct and the alterations in postganglionic neuronal membrane properties appeared to be mediated by several ionic mechanisms. If these studies were analogous to pieces in a puzzle to understand the effects of PACAP in sympathetic development and function, the picture of late has been more completely assembled. But several important challenges still remain. What are the signal transduction mechanisms that mediate the PACAP-induced changes in sympathetic membrane properties? How do the resulting alterations impact the acute and more long-term responses of sympathetic neurons? Does the coupling of PACAP1 receptors to intracellular signaling pathways differ during development, resulting in a transition from the neurotrophic properties of PACAP in neuroblasts to neuromodulatory roles of the peptides in postmitotic neurons? By looking at these issues in one distinct neuronal system, we enlarge our understanding and appreciation of peptides, and PACAP in particular, in the molecular and cellular events guiding neuronal development, function, and plasticity.